The compounds of formula (I)

wherein R1 is selected from the group consisting of hydrogen and C1-4alkyl and wherein X, R3, R4, R5 and R6 are as hereinafter defined, are known compounds that have been found to exhibit anticonvulsant activity and are therefore useful in the treatment of conditions such as epilepsy. These compounds are disclosed in U.S. Pat. No. 4,582,916 and U.S. Pat. No. 4,513,006, which also disclose processes for the preparation of said compounds; and which are hereby incorporated by reference.
One process disclosed in the above referenced patents is a process for the preparation of the compounds of formula (I) comprising reacting an alcohol of the formula RCH2OH with a chlorosulfamate of the formula ClSO2NH2 or ClSO2NHR1 in the presence of a base such as potassium t-butoxide or sodium hydride at a temperature of about −20° C. to 25° C. and in a solvent such as toluene, tetrahydrofuran or dimethylformamide, where R is a moiety of the formula (II)

This process has two major disadvantages. One disadvantage is that the process calls for a combination of NaH and DMF which has an uncontrollable exotherm and is therefore potentially explosive. See J. Buckley et al., Chemical & Engineering News, Jul. 12, 1982, page 5; and G. DeWail, Chemical & Engineering News, Sep. 13, 1982. Another disadvantage is that the process also uses highly toxic and corrosive chlorosulfonyl isocyanate (CSI) to prepare the commercially unavailable sulfamyl chloride (ClSO2NH2). The CSI is not only difficult to work with, because of its toxicity and corrosiveness, but also is available from only limited suppliers.
Another process for the preparation of compound of formula (I) disclosed in the above mentioned U.S. Pat. No. 4,513,006 comprises reacting an alcohol of the formula RCH2OH with sulfuryl chloride of the formula SO2Cl2 in the presence of a base such as triethylamine or pyridine at a temperature of about −40° C. to 25° C. in a diethyl ether or methylene chloride solvent to produce a chlorosulfate of the formula RCH2OSO2Cl2. The chlorosulfate of the formula RCH2OSO2Cl2 may then be reacted with an amine of the formula R1NH2 at a temperature of about −40° C. to 25° C. in a methylene chloride or acetonitrile solvent to produce the compound of formula (I). This process utilizing diethyl ether, methylene chloride and acetonitrile solvents produces relatively low yields of the desired end product of formula (I).
A third process disclosed in the two patents mentioned above comprises reacting the chlorosulfate of formula RCH2OSO2Cl2 formed as previously described with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile to yield an azidosulfate of the formula RCH2OSO3N3. The azidosulfate is then reduced to the compound of formula I wherein R1 is hydrogen, by catalytic hydrogenation.
The disadvantage with this process is that explosions may occur when handling the azide compounds. Also, the process contains an additional chemical transformation involving the reduction of the azide to the NH2 moiety.
Maryanoff et al. in U.S. Pat. No. 5,387,700 disclose a process for the preparation of compounds of formula (I) which comprises reacting an alcohol of the formula RCH2OH with sulfuryl chloride in the presence of a base, in a solvent selected from the group consisting of toluene, t-butyl methyl ether and tetrahydrofuran, to form a chlorosulfate intermediate of the formula RCH2OSO2Cl2. The chlorosulfate of formula RCH2OSO2Cl2 is reacted with an amine of the formula R1NH2, in a solvent selected from the group consisting of tetrahydrofuran, t-butyl methyl ether and lower alkanol (e.g. methanol or ethanol) to form the compound of formula (I).
One disadvantage of this process is that the compound of formula (I) is prepared in a batch process wherein the first reaction is carried out, the solvent is removed, the product is isolated, the isolated product is re-dissolved in a second solvent and then reacted to form the final product. This results in a process which requires isolation of a semi-stable, thermally labile ROSO2Cl intermediate. Additionally, this process requires handling of multiple solvents and multiple solvent recovery processes for recycling or disposal resulting in a process which is both cost and labor intensive.
It is an object of the present invention to provide a one step process for the preparation of the compounds of formula (I), a process which uses readily available materials, can be carried out without isolation of intermediates and/or produces relative high yields, thereby allowing for commercial production of the compounds of formula (I).